1. Field of the Invention
The present invention relates to aromatic cyclic alkylethers. More particularly, the present invention relates to the novel compounds of Formula I, which inhibit cyclooxygenase I and/or II, to pharmaceutical compositions containing one or more of these compounds in combination with a pharmaceutically-acceptable carrier, and to medical methods of treatment employing these compounds.
2. Background Information
It is well recognized that arachidonic acid, an essential unsaturated fatty acid, is enzymatically oxygenated to various products, including, prostaglandins, thromboxanes, the 5-, 11-, 12- and 15-hydroxyeicosatetraenoic acids (HETEs, DIHETEs) and hydroperoxyeicosatetraenoic acids (HPETEs), and the leukotrienes, all of which have potent physiological effects.
Those compounds of the present invention which inhibit cyclooxygenase I and/or II inhibit the synthesis of prostaglandins via the cyclooxygenase pathway of arachidonic acid metabolism. These prostaglandin synthetase inhibitors may exhibit anti-inflammatory, anti-pyretic and analgesic activity, and are useful in the treatment of inflammatory conditions such as arthritis.
Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG.sub.2, PGH.sub.2 and PGE.sub.2, and have been a common target of anti-inflammatory drug discovery. However, common nonsteroidal anti-inflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDS have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). Recently, the sequence of another heretofore unknown enzyme in the human arachidonic acid/prostaglandin pathway has been reported by T. Hla and K. Nielson, PROC. NATL. ACAD. SCI. USA, 89, 7384 (1992), which is incorporated herein by reference, and named cyclooxygenase II (COX II) or prostaglandin G. H. synthase II. The discovery of an inducible enzyme associated with inflammation provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects. Cyclooxygenase II is inducible by cytokines or endotoxins, and such induction is inhibited by glucocortoids (J. Masferrer, et al, PROC. NATL. ACAD. SCI. USA, 89, 8917 (1992), which is incorporated herein by reference). The 6-methoxy-2-napthylacetic acid metabolite of nabumetone has been found by E. Meade et al. to selectively inhibit the COX II enzyme (J. BIOL. CHEM., 268, 6610 (1993), which is incorporated herein by reference). In addition, Futaki et al (GEN. PHARMAC., 24, 105 (1993), which is incorporated herein by reference,) has reported that N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide is anti-inflammatory and lacks gastric side effects.
Compounds of the present invention relieve the effects of inflammation and may inhibit cyclooxygenase I and/or cyclooxygenase II.
Prior to the recognition of the significance of the arachidonic acid metabolism pathway in allergic reactions and inflammation, the search for effective therapeutic agents was based primarily on those agents which treated the symptoms of allergy and inflammation. There has since been an effort to develop new drugs which selectively block the formation of the mediators of these conditions, and the present invention provides new chemical entities which are inhibitors of the arachidonic acid pathway and are useful in the treatment of asthma, rheumatoid arthritis, osteoarthritis, psoriasis, and other allergic, hypersensitivity, and inflammatory conditions. Further examples of inflammatory conditions or diseases with an inflammatory or immune system component are disclosed in, for example, the Merck Manual of Diagnosis and Therapy, 15th Edition (1987) which is incorporated herein by reference.
Various thioether compounds have been described previously. For example, U.S. Pat. No. 4,711,903 and its continuation-in-part, U.S. Pat. No. 4,755,524, disclose compounds of the formula: ##STR2## wherein: R.sub.1 and R.sub.2 are the same or different and independently represent tert-alkyl or phenyl; A represents methylene or methylene substituted by alkyl, dialkyl or hydroxy, provided that when A includes hydroxymethylene, the hydroxymethylene group is not adjacent to a heteroatom; B represents sulfur, sulfoxide, sulfone, oxygen, --NH-- or nitrogen substituted by alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl; C represents methylene or methylene substituted by alkyl; R.sub.3 represents CO.sub.2 H, CO.sub.2 -alkyl or a tetrazole group; m is 0 or 1, n is 2, 3 or 4 and p is 1, 2 or 3; and the pharmaceutically acceptable salts thereof. The compounds are specific inhibitors of 5-lipoxygenase, and are useful in the treatment of local and systematic inflammation, allergy and hypersensitivity reactions and other disorders in which agents formed in the 5-lipoxygenase metabolic pathway are involved.
U.S. Pat. No. 4,621,098 and its equivalent, European Patent Application Publication No. 0131221, disclose compounds of the formula: ##STR3## in which Ar is phenyl or phenyl substituted by one to three of varied substituents, for example, alkyl, alkoxy, hydroxy, etc.; Q is oxygen, sulfur or an NH group; A is straight or branched chain, optionally substituted, alkylene, and R is hydrogen or straight or branched alkyl, optionally substituted by alkoxy, hydroxyl, carboxyl, alkoxycarbonyl, etc.; and n is 0, 1 or 2. The disclosed compounds are indicated to have anti-inflammatory and anti-allergic properties through inhibition of undefined anaphylactic and anaphylactoid reactions, although no test data are provided. The preferred compounds are stated to be those in which Q represents oxygen and n is 0, without mention of any preference among the numerous possible substituents for R or substituted phenyl as Ar.
U.S. Patent Nos. 4,029,812, 4,076,841 and 4,078,084 disclose compounds of the formula: ##STR4## comprising 2-(3,5-di-tert-butyl-4-hydroxy-phenyl) thio carboxamides. The compounds are indicated to be useful in lowering serum cholesterol and triglyceride levels.
A series of thioethers, useful as, for example, polyfunctional antioxidants for polymers, and biologically active substances, obtained by the nucleophilic addition of thiols, including 3,5-di-tert-butyl-4-hydroxythio-phenol, and hydrogen sulfide to acrylate derivatives have been described. See Medvedev et al., Khimiya; Khimicheskaya Tekhnologiya, Volume 20, (1977), pp. 568-574. The compounds resulting from the foregoing process have the general formulas RS(CH.sub.2).sub.n X and S(CH.sub.2 CH.sub.s X).sub.2 in which R is 3,5-di-tert-butyl-4-hydroxyphenyl and X represents, for example, --C.ident.N, NH.sub.2, CH(OH)CH.sub.2 Cl, OH, COCl and various carboxy, carboxylate and amide functions.
U.S. Pat. No. 4,153,803 discloses cholesterol-lowering phenoxyalkanoic acid esters of the formula: ##STR5## wherein, when Y is sulfur, X is hydrogen, benzyl, benzyloxy or benzylthio or substituted derivatives thereof; R is hydrogen, halogen, hydroxy, alkyl or alkoxy, A.sup.1 and A.sup.2 are hydrogen or alkyl and Z is amine or azacyclohydrocarbonyloxy.
JP 49116035 discloses a process for making compounds of the formula: ##STR6## wherein R.sup.1, R.sup. 2, R.sup.3 and R.sup.4 are hydrogen, alkyl or aryl groups, and R.sup.1 and R.sup.2 can be combined to form a cycloalkyl group. The compounds are said to be useful as drug intermediates, agricultural chemicals, antioxidants and industrial chemicals. Specifically disclosed is a compound of the formula: ##STR7##
CA 107:197783q discloses dialkylphenol derivatives of the formula: ##STR8## wherein R.sup.1 R.sup.2 =alkyl; A=alkylene, S, SO; Y=alkoxyimino, O; Z=alkylene, O; n=1, 2; 2-3 saturated or unsaturated. The compounds are said to be useful as modifiers for biosynthesis of prostaglandins and leukotrienes and hypolipemics (no data).
EP0293900 discloses 5-lipoxygenase inhibiting compounds of the formula: ##STR9## where R.sup.3 and Y together are: ##STR10## and n is 2 or 3.
Katsumi, et al., CHEM. PHARM. BULL. 34(4):1619-1627(1986) discloses 3,5-di-tert-butyl-4hydroxystyrenes. Some of the compounds disclosed had anti-inflammatory activity and some inhibited 5-lipoxygenase. Only one compound (Compound 3, Table I) had S attached to the 3,5-di-tert-butyl-4-hydroxyphenol. It has the following structure: ##STR11##
U.S. Pat. No. 4,801,611 discloses 5-lipoxygenase inhibitors of the formula: ##STR12## where R.sub.1 and R.sub.2 are tert-alkyl and R.sub.3 can be: ##STR13## where R.sub.6 and R.sub.7 are C.sub.1-4 alkyl.
Each of the documents described hereinabove discloses compounds which are structurally different from the compounds of the present invention. Thus, the compounds of the present invention are structurally distinct from that which has been described in the art.
Compounds of the present invention inhibit cyclooxygenase I and/or cyclooxygenase II, and relieve the effects of inflammation. These compounds, in addition, produce a reduced amount of side effects.